First Results Posted from the DCM DNA Gene Mutation Test !!

Unread postby von Cosack Dobermann » Wed Apr 27, 2011 11:21 pm

As I said to Bitten, when you wake valencia up you can understand him and he will and can make sence. I agree with what your saying but when you speak in riddles no one will take you serious unless your writing for a grade in a class.
I do NOT breed now and my last litter was in 1977 so I have left the breed in your capable hands, and ofcourse your circle. In regards to health issues follow what Bitten is suggesting because shes aware of the current tests and how they have failed or succeeded. This will give you more time to elaborate on your riddle writing skills. Good nite. Von
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Unread postby Weinberge » Thu Apr 28, 2011 6:17 am

From that years till today many things was changed.
In 1970 years America breed Honor Guards from great Borung the Warlock . Today Warlock name was destroyed and used in an improper mode to name improper dobermanns .

....erased
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Unread postby Ronindobe » Thu Apr 28, 2011 6:21 pm

Altho I am disconcerted that the main papers of Meurs and Wess have not been published [I am not sure why...but this work must pass peer review...if it doesn't it requires more inspection], I can not agree that the WSU test is a "waste" of money. It certainly can not be used to determine that a dog will never develope DCM and that is no suprise given the likelihood of either polygenetic modality or several different paths leading to the same end. Sonia's chi squared analysis is correct on the given sample results. There may another more statistically determinate gene yet to be identified. It is my hope the work will continue with intensity. But the gene identified by Meurs is still an aberrant mutation of a protein with an important function and attempts should be made to identify it in breeding stock and to eliminate it from the gene pool. However it is not proving to be of penultimate concern and other considerations in selection by experienced, knowledgable breeders may take presidence. In the list of available tests that the Dobermann should receive in breeding selection currently other information comes first, being more definitive. It is not a "waste" of money, but with limited funds perhaps not a high priority. However at $60usd it is not that expensive compared to the asking prices of well bred pups. In general any negative mutation that can be identified and filtered out, should be.

Alin, I know Mr. Cosack and correspond with him almost daily. You must understand that sometimes your writing, perhaps when translated to English, is muddy and the point is not often clear. Most of the ideas come through by the constant repeating of the same line of thought. Altho some of us may question your theories, no one questions your passion for attempting improvement. But as to respect.... Mr. Cosack is a rawhide tough man who has trained Dobermann for actual personal protection and civil service work for longer than you have been alive. This was his profession. His dogs actually were called upon to protect the lives of their handlers under extreme confrontation, not in a staged competition. His knowledge of the changing character and utlility of the breed since the 60's is first hand and deep. He is a master trainer and his advice is sought and valued by many, myself included. I have the highest regard for him. I am fortunate to have people like Von and Bitten to improve my thinking on the Dobermann [they don't always agree, of course :wink: ]. Plus he is a rascal...and is playing with you to learn your character.

8)
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Unread postby Weinberge » Thu Apr 28, 2011 6:34 pm

I do not contested Cosak past performance and I believed that he can breeded a beautiful dobermann in past.

If for you the English is native language, I accept that my English is not so good and is not easy to talk in other language.
But he talk with me without respect without to understood exactly my arguments.


Regard if he play with me to know my character, if he knowed in past what mean a American Honor Guard dobermann breeder (true dobermann not actual surogates), is not necessary to play something for know my charcater. Because he must to know that the dobermann is like their breeders character.
....the bigest problem of health and character of our dobermanns is the breeders missing character.

A Honor Guard will remain a Honor Guard till the death or genetical extinction .

I will consider that discussion a missunderstanding and I correct my posts.
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Unread postby Ronindobe » Thu Apr 28, 2011 9:03 pm

It is true that the best owners and breeders of the Dobermann are very much like their favored breed!! In this way both you and Mr. Cosack [and myself] are much the same... :shock: :lol:

Răspunsul dumneavoastră este corect şi bine gândite. Eu vă mulţumesc pentru asta. Noroc ca întotdeauna cu Dobermann dumneavoastră şi planurile. Avante "!

8)
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Discovered a new risk allele in chromosome 5 DCM associated

Unread postby Sonia Dobe » Sat Jun 04, 2011 10:37 am

A research group from Institute of Genetics (University of Bern), Clinic of Small Animal Medicine (LMU University Munich), Department of Medical Biochemistry and Microbiology (Uppsala University) and Small Animal Teaching Hospital (University of Liverpool) has discovered a new risk allele DCM-associated (allele C: g.53,941,386T>C ) in exon 10 of CFA5 in the zone of HAS-1 gene, that explains the arrhythmia cases (half cases).

Trial group include 71 affected Dobermann and 70 Dobermann controls from Germany, but results are contrasted with a group of 15 affected Dobermann and 24 Dobermann controls from UK (total 86 DCM cases and 94 control). Results reveal that phenotypic manifestations of DCM in arrhymias and dilated signs are controlled by different genetic factors, and confirm a polygenic control on Dobermann DCM.

Article:
Mausberg T-B, Wess G, Simak J, Keller L, Drögemüller M, Drögemüller C., Webster M.T., Stephenson H., Dukes-McEwan J., Leeb T. (2011). A Locus on Chromosome 5 Is Associated with Dilated Cardiomyopathy in Doberman Pinschers. PLoS ONE 6(5): e20042.

The hyaluronan synthase 1 (HAS-1) gene encodes a plasma membrane protein that synthesizes hyaluronic acid (HA), an extracellular matrix molecule that provides a framework for ingrowth fibroblasts. In addition, the interaction of HA with the leukocyte receptor CD44 is important in tissue-specific homing by leukocytes as neutrophils.

Obviously this discovery reveals the complexity of Dobermann DCM, and changes our perspective in relation with significance of PDK4 mutation and WSU DNA test in risk evaluation of DCM and breeding strategies.
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Unread postby kansadobe » Sat Jun 04, 2011 2:01 pm

Thank you for the post. Is it possible for you to translate this development into common language? :D :?
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Unread postby jotunheim » Sat Jun 04, 2011 3:16 pm

Doug

As I understand Sonia's entry, plus having read the paper - the discovery of the mutated gene by the Germany group = that there are more than one mutated gene that might cause development of DCM.
From the entry, and the paper - the mean of accuracy on the German findings is approx 50%, which again leads to, that this finding is not a definitive / conclusive DNA test, which is equal to the findings of K. Meurs.
As both the US and German groups says, that their findings are of autosomal dominant heritage - the individual mutated gene might be such, but as an overall, the total picture = that the problem seems likely to be polygenetic, as there's now been found 2 mutations.

I know, your question wasn't directed to me, but to Sonia, still I hope you don't mind me throwing in my personal understanding of the situation and the paper from Germany, which has been made public.
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Unread postby jotunheim » Sat Jun 04, 2011 9:46 pm

Here's the link to the published paper on the Germany findings - Link: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020042
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Unread postby Sonia Dobe » Sun Jun 05, 2011 11:38 am

kansadobe wrote:Thank you for the post. Is it possible for you to translate this development into common language? :D :?


Hi Doug:

Bitten has resumed well the scenario: two mutations (for the time being) interact to configure the DCM phenotype, which reveals a polygenic control of Dobermann DCM. For understand the significance of this scenario we can look the Punnett square for two genes (four alleles) at random combinations: PDK4 gene (“D” mutant allele- “d” wild allele) and HAS1 gene (“A” mutant allele-“a” wild allele)

Image

93.75 % of combinations content at least one dominant mutation
56.25 % of combinations content both dominant mutations
Only a 6.25% of combinations are clears for both dominant mutations

We don’t know what genotypes are dangerous and the frequency of both mutant alleles in the population. However, we can have an idea of the extension of dangerous genotypes in the population taking account the prevalence of DCM (58.2%) and the incomplete penetrance of disease (more than 58.2% of individuals content dangerous genotypes). Nor do we know which genetic or environmental factors modulate the penetrance of dangerous phenotypes.

There notice of DCM cases in Dobermann population from twenties, before the split of population among European and American branches. It is reasonable to assume that both families share the same pattern of inheritance. The contrast of the new mutation with a group of UK Dobermanns confirms this point.
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Unread postby js_finland » Sun Jun 05, 2011 1:36 pm

"Our findings that approximately half of the DCM affected Doberman Pinschers carry the risk-allele on CFA 5 indicate that this is a major, but not the only genetic risk factor for DCM in this breed. The lack of other association signals further suggests that the unexplained 50% DCM cases might be caused by several different genetic risk factors of small effect size, which cannot be detected with the currently available cohort sizes."

It seems that the European group doesn't put too much value on the WSU/VSGL findings of a mutation in a part of the genome encoding PDK-4 - their interpretentation is it's just one of the several different risk factors (which should not even have been detected with the currently available cohort sizes...) each having just a small effect on DCM in dobermans. It would be really interesting to see if/how the WSU/VSGL team will react...
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Unread postby jotunheim » Sun Jun 05, 2011 1:51 pm

js_finland wrote:"Our findings that approximately half of the DCM affected Doberman Pinschers carry the risk-allele on CFA 5 indicate that this is a major, but not the only genetic risk factor for DCM in this breed. The lack of other association signals further suggests that the unexplained 50% DCM cases might be caused by several different genetic risk factors of small effect size, which cannot be detected with the currently available cohort sizes."

It seems that the European group doesn't put too much value on the WSU/VSGL findings of a mutation in a part of the genome encoding PDK-4 - their interpretentation is it's just one of the several different risk factors (which should not even have been detected with the currently available cohort sizes...) each having just a small effect on DCM in dobermans. It would be really interesting to see if/how the WSU/VSGL team will react...


Jukka

I do not really understand what you are getting at - as I see it, we now have 2 mutations related to DCM => DCM being of polygenic nature, regardless that the mutations invididually might be autosomal dominant.

Are you saying, that the people behind the German paper, should make recommandations in regard to the WSU findings ? Findings which haven't even been published, findings which haven't been published under peer review recognision ... No paper, no proper information = you can't make references and even less recommandations ... whether you want to or not.

As said - we now have 2 mutations, and these have been found on 2 different chromosomes, and according to what I know and understand, these 2 mutations do not complement oneanother.
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Unread postby Ronindobe » Sun Jun 05, 2011 7:49 pm

Of course the stat analysis figure of 56.25% with at least one mutant copy of each starts to resemble the estimates of 58.2% population prevallence. Seems a quick responsible next project would be to close analyze the Wess samples with the WSU DNA test...the reverse would be nice but having at this point only skimmed the article, I have not seen a clear DNA test offered by the Wess lab. I wonder what chances of collaboration there are? Can anybody come up with a estimation of reported "young dog drop over" [say under 4 years]? Suppose it might be as high as 6+%?
It would also seem to appear that some other mitigating factor(s) may be in play yet. Perhaps a trigger or modulator skewing penetrance...or perhaps it is these identified genes which act in this manner. I don't think we are done yet....
I am a bit confused tho as to why if both labs were analysing across all the chromosones ...why didn't each see the other mutation? Is it a matter that the stopped at the first one they noticed? Any thoughts on this Sonia?
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Unread postby js_finland » Mon Jun 06, 2011 1:35 pm

jotunheim wrote:Are you saying, that the people behind the German paper, should make recommandations in regard to the WSU findings ?


No, I'm just wondering what's going on and (like Ronindobe already wrote) how is it possible the two groups did not even notice (or at least admit that in public) the other mutation considered as a major one by their colleagues on the other side of the Atlantic Ocean.

Ronindobe wrote:I am a bit confused tho as to why if both labs were analysing across all the chromosones ...why didn't each see the other mutation? Is it a matter that the stopped at the first one they noticed? Any thoughts on this Sonia?


"We detected a genome-wide significant association on canine chromosome 5 (CFA 5). ... There were no significant associations on any of the other chromosomes."

Doesn't this mean at least the other group has looked at every possible location? And I suppose the other one has done that too.
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Unread postby jotunheim » Mon Jun 06, 2011 4:46 pm

Jukka

->
"We detected a genome-wide significant association on canine chromosome 5 (CFA 5). ... There were no significant associations on any of the other chromosomes."
<-

First of all - you need to know, that I'm not sure IF I have understod the paper, but as I understand, the German publication is primary connected to research connected to arrythm - hence the statement "could" be with reference to this area. Merely guessing though ....
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